Novel NOTCH3 alteration expanding the molecular spectrum of pericytic tumours: report of two cases

TL;DR

This paper reports two myofibroma cases with a new NOTCH3 gene alteration, suggesting a new mechanism in pericytic tumor development and potential treatment options.

Contribution

The study identifies a novel NOTCH3 internal tandem duplication as a new molecular alteration in pericytic tumors.

Findings

RNA sequencing revealed a NOTCH3 ITD in two myofibroma cases.

The NOTCH3 alteration affects the C-terminal heterodimerization domain.

Myofibromas with ITDs cluster separately from conventional cases.

Abstract

Myofibromas are part of the pericytic tumour family, which includes myopericytomas, glomus tumours and angioleiomyomas. While they typically display benign behaviour when arising in the skin and subcutaneous tissues of the head and neck, rare aggressive variants have been reported, particularly those with visceral or intracranial involvement. The most frequently identified molecular alterations in myofibromas are PDGFRB gain‐of‐function mutations, primarily single‐nucleotide substitutions.

Herein, we report two cases of myofibroma: one aggressive case with central nervous system involvement in a newborn, exhibiting a monophasic morphology, and a second, subcutaneous case in an adult. RNA sequencing was performed on both tumours, and data analysis was conducted using a four‐pipeline fusion‐calling approach (Arriba, FusionCatcher, FusionMap and STAR‐Fusion). This analysis identified a novel somatic internal tandem duplication (ITD) in the NOTCH3 gene, affecting exons 26 and 27, specifically involving the C‐terminal heterodimerization domain of the NOTCH3 receptor. Unsupervised hierarchical clustering demonstrated that myofibromas with ITDs segregate distinctly from conventional myofibromas and other pericytic tumours.

Our findings suggest that NOTCH3 ITDs represent a novel oncogenic mechanism in pericytic tumour pathogenesis, likely driving constitutive activation of the NOTCH signalling pathway. Given the potential therapeutic relevance, particularly in aggressive or life‐threatening cases with CNS involvement, our findings highlight the importance of extensive molecular profiling. Targeted therapy with NOTCH inhibitors may represent a promising strategy in the management of aggressive cases of ITD‐driven pericytic tumours.

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